BSA-assisted synthesis of nanoreactors with dual pH and glutathione responses for ferroptosis and photodynamic synergistic therapy of colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in global incidence and second most common cancer in global mortality rates, accounting for 10% of all cancer cases and 9.4% of all cancer-related deaths. CRC is a heterogeneous disease, mostly comprising sporadic tumors. Approximately 19%–28% of patients have postoperative metastasis. In this study, we report an epigallocatechin gallate (EGCG)-based metal polyphenol network (MPN) with CD44 targeting, glutathione (GSH) sensitivity and pH response for the codelivery of the photosensitizers chlorin e6 (Ce6) and Fe3+. Photodynamic therapy (PDT) has become a potential clinical treatment method because of its noninvasive nature, low toxicity and spatiotemporally controlled treatment capability. Ferroptosis is a nonapoptotic cell death caused by peroxidative modification of phospholipid membranes via iron-dependent mechanisms. We unified ferroptosis and PDT into a nanoreactor (BSA-Ce6@MPN, BCM) to treat CRC. In vitro analysis showed that laser-irradiated BCM increased the cellular reactive oxygen species (ROS) and lipid peroxide (LPO) contents and decreased the expression levels of GSH and glutathione peroxidase 4 (GPX4). BCM-mediated ferroptosis and PDT synergistic therapy were significantly effective in the CT26 tumor-bearing mouse model, demonstrating the efficacy of the combination therapy. These results suggest that the nanoreactor for the synergistic treatment of ferroptosis and PDT holds great promise for clinical translation.